tbuckley/cabot-search huggingface dataset:
Demographic analysis of diagnostic patterns in head and neck fibromyxosarcoma.
Authors: Harvey Wang, Beau Hsia, Xinxin Wu, Erin Sinai, Peter T. Silberstein, Darby Keirns
Journal: Journal of Clinical Oncology (2023)

e23546 Background: Fibromyxosarcoma (MFS) is a rare form of cancer that originates in connective tissue, starting in the arms and legs, but spreads into healthy tissues elsewhere in the body. 42% of MFS patients succumb to the disease within 5 years of diagnosis, with most cases being fatal in less than 2 years post-diagnosis. Due to the scarcity of literature regarding MFS, with no prior otolaryngological study on MFS, the diagnostic trend of the disease can assist in understanding its epidemiology. To determine diagnostic patterns, demographic factors of head and neck MFS patients in the National Cancer Database (NCDB) were analyzed. Methods: Using the National Cancer Database (NCDB) data from 2004 – 2020, a retrospective analysis was performed that included patients with a histologically-confirmed MFS diagnosis in the head and neck (N = 67). Descriptive statistics were used to analyze demographic factors: age, sex, race, social status, number of surgical procedures, facility type, insurance status, Charleson-Deyo score, and type of palliative care received. Regression analysis was used to interpret incidence trends. Results: 67 total patients were identified in NCDB with head and neck MFS between 2004 – 2020 with a steady amount of diagnoses per year (R2 = 0.093). The top primary site was the maxillary sinuses (22.4%). The average age of diagnosis was 54.1 years (SD = 18.0, range = 10 – 90 years). MFS was more present in males (59.7%) than females (40.3%). The majority of the patients were non-Hispanic White (82.1%). More patients lived in counties of metropolitan areas of a population of 1 million or more (55.2%) than in other urban/rural areas (13.5%). 82.1% of patients underwent surgical procedures at the primary site, with 28.4% being through a primary incision in the nose. More patients were treated in an academic/research program (52.2%) than in a non-academic program (28.4%). Most of the patients were privately insured (59.7%). More patients had a median income in the top quartile (44.8%) compared to patients in the second, third, or fourth quartiles. Most individuals had a Charlson-Deyo score of 0 (82.1%). The majority of the patients did not receive palliative care (97.0%). Conclusions: This is the first analysis of otolaryngological MFS using the NCDB, which expands our knowledge on the sociodemographic factors associated with its diagnosis. From all the years analyzed, MFS remains a rare disease. The majority of patients diagnosed with MFS tend to be non-Hispanic, White males with the primary site in the maxillary sinus. MFS patients are mostly treated in academic/research programs and live in densely-populated areas. This analysis provides an initial overview of the impact of demographic factors in patients with MFS, but examination into the impact of these variables on the prognosis and outcome of MFS patients would be valuable in understanding the social inequity surrounding this malignancy.
Serum IL-6 levels following siltuximab administration in castleman disease.
Authors: Natalie Mango, Saishravan Shyamsundar, Mateo Sarmiento Bustamante, Criswell Lavery, Sheila K. Pierson, Frits van Rhee, David Fajgenbaum
Journal: Journal of Clinical Oncology (2023)

e19545 Background: Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder. Though etiology is unknown, interleukin-6 (IL-6) is a driver in a portion of cases. Siltuximab is a monoclonal antibody that targets IL-6 and has been approved by the Food and Drug Administration to treat iMCD. Treatment guidelines for iMCD note that IL-6 directed therapy can result in spurious elevation of serum IL-6, based on anecdotal reports. This could lead physicians to erroneously infer treatment failure. Herein we investigate an international natural history registry of CD to evaluate whether IL-6 levels are increased following siltuximab. Methods: Data on peak IL-6 levels measured in patients before and after receiving siltuximab was available for 40 patients. C-reactive protein (CRP) levels measured near peak IL-6 values before and after siltuximab were also collected where available (n=32). Peak IL-6 values were standardized by the upper end of the reference range. Median values and interquartile ranges were calculated for pre- and post-siltuximab CRP and peak IL-6 values. Wilcoxon signed-rank tests were used for statistical comparison. Results: Our cohort consisted of 40 patients who had lymph node histopathology consistent with Castleman disease. An expert panel confirmed 16 iMCD, 5 POEMS-MCD, 1 regional CD, 3 unicentric CD, 11 other diagnoses, and 4 remain to be determined. Breakdown by gender was 50% male (n=20) and 50% female (n=20) with a mean age of 40.76 years. We analyzed peak standardized IL-6 levels before and after treatment with siltuximab. Prior to treatment with siltuximab, the median IL-6 level was 3.18, whereas after treatment with siltuximab, the median IL-6 level was elevated to 557 (p = 1.8 x 10 -12 ). Given that CRP is a well-established biomarker of IL-6 activity, we investigated whether the increased IL-6 was a reflection of increased disease activity in these patients. Here, we found that median CRP before treatment was 59.7 mg/L, whereas after treatment, median CRP decreased to 4.95 mg/L (p = 0.0005) suggesting that IL-6 levels were rising despite reduced disease activity. IL-6 levels rose almost 200-fold while CRP reduced over 10-fold. Conclusions: Our results indicate that IL-6 levels significantly increase after patients receive siltuximab. Given that CRP is a biomarker of IL-6 activity, we infer that IL-6 is artificially elevated but not having a functional impact in the patient. Therefore, IL-6 levels should not be measured after siltuximab is given and they should not be used to guide treatment decisions. [Table: see text]
Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC).
Authors: Joyce F. Liu, Siqing Fu, Gary Edward Richardson, Zivko Vranjes, Tarek Meniawy, Catherine M. Shannon, Erika P. Hamilton, Stephanie V. Blank, Cara Amanda Mathews, Jasmina Alidzanovic, Rossitza Krasteva Ruseva, Qing Shi, Olivier Harismendy, Ann M. Ptaszynski, Shannon Neville Westin, Funda Meric-Bernstam, Premal H. Thaker
Journal: Journal of Clinical Oncology (2023)

5513 Background: Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor demonstrating single-agent antitumor activity. Azenosertib may inhibit CT-induced DNA damage repair and provide benefit in pts with platinum R/R EOC. Cyclin E1 amplification/overexpression is present in ≥35% of metastatic ovarian cancer. High expression/amplification of Cyclin E1 is a poor prognostic marker and predictive of lack of response to platinum-based CT. Ovarian models overexpressing Cyclin E1 have exquisite sensitivity to azenosertib in vitro and in vivo; forced Cyclin E1 overexpression sensitizes cell lines with low endogenous Cyclin E1 to azenosertib. Methods: This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Primary endpoint is safety and identification of RP2D of each combination. Secondary endpoints include clinical activity. Azenosertib was given continuously or intermittently QD in 21 or 28D cycles until PD or unacceptable toxicity. Results: 103 pts were enrolled; at data cut-off, 94 were efficacy evaluable. 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the highest ORR [9/18 (50%)], followed by Carbo [9/27 (33.3%)]; ORR for azenosertib + PLD or + GEM was 14.3% (5/35, 2/14 respectively). 80 pts had available Cyclin E1 expression data by IHC; higher Cyclin E1 (H-score &gt;50) correlated with higher ORR and longer PFS (ORR = 31.3% vs 7.7%; PFS = 10.35 vs 3.25 mo, HR=0.3; Table). Frequent Grade ≥3 TEAEs (%) were neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1). Conclusions: Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC. Clinical trial information: NCT04516447 . [Table: see text]
Differential overall survival and treatment for non-dedifferentiated liposarcoma in academic and non-academic facilities: An NCDB analysis.
Authors: Alec Czaplicki, Christopher Bine, Eric Nielson, Marco Braaten, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2023)

e23556 Background: Liposarcoma is a malignant soft tissue tumor sarcoma which most commonly arises in subcutaneous fat of the limbs and abdomen. Previous studies found overall survival and treatments to vary between patients treated at academic and non-academic facilities. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with non-dedifferentiated liposarcoma from 2004 to 2019 using the histology codes 8850, 8851, 8852, 8853, 8855, and 8857 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA, Chi-Square, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: Of the 15,256 patients queried, 72% were treated at an academic/research facility (AF). Patients treated at an AF had an improved median survival compared to a non-academic facility (NA) (184 months versus 154 months; p &lt; 0.001). After controlling for stage, income, and therapy type, treatment at an AF was associated with an independent decrease in hazard (HR = .824; p &lt; 0.001). AF patients disproportionately came from a higher income bracket and were more likely to carry private insurance. Additionally, AF patients were more likely to receive surgery, have margins with complete tumor resection, and receive adjuvant chemotherapy (p &lt; 0.001). There were no significant differences in stage or metastasis at presentation between the two groups. Conclusions: Patients with non-dedifferentiated liposarcoma treated at an academic/research facility had improved overall survival, higher rates of surgery, higher rates of chemotherapy, and better surgical margins compared to patients treated at a non-academic facility.
Predictive molecular markers of chemoradiation resistance in cervical cancer.
Authors: Prashant Kumar, Richa Chauhan, Irene A George, Sewanti Atul Limaye, Rengaswamy Sankaranarayanan, Ekta R Dhawale, Moni Kuriakose, R Venkataramanan
Journal: Journal of Clinical Oncology (2023)

e17505 Background: Cisplatin based concurrent chemoradiation therapy (CCRT) has been recognized as the standard treatment for locally advanced cervical cancer. Although patients treated with CCRT have better chances of survival and prognosis, over 30–40% of patients do not achieve a complete response and may develop locoregional recurrence. Hence predictive biomarkers-based treatment selection of right cohort could be a strong approach for personalized treatment. Therapy resistance occur due to multifactorial events and targeting key molecules involved in treatment resistance could combat treatment resistance. Herein, we profiled both the global proteomic and phosphoproteomic landscape of the concurrent chemotherapy resistant cervical cancer to identify potential predictive biomarkers as well as therapeutic targets. Methods: We employed mass spectrometry based global proteomic and phosphoproteomic strategies to identify proteomic signature and dysregulated kinase involved in CCRT resistance. The biopsy tissue samples were collected before the start of the therapy and the protein was extracted, digested from each sample and labelled with 10 plex TMT (Tandem Mass Tags). The pooled peptides were fractionated by basic pH liquid chromatography analyzed on Orbitrap-Fusion-Tribrid mass spectrometer (ThermoFisher Scientific). For the phosphoproteomic experiment, the peptides were enriched using IMAC based phosphopeptide enrichment method. Liquid chromatography-mass spectrometry/ experiments together with thorough bioinformatics analysis were carried out to characterize the global proteome and phosphoproteome. Results: Analysis of protein expression and phosphorylation led to the identification of dysregulated protein expression and phosphorylation between treatment sensitive and resistant patient cohorts. Further analysis and validation experiment revealed the potential of differentially expressed protein syntaxin 3 (STX3) as a predictive biomarker for treatment resistance. Phosphoproteomic analysis revealed the enrichment of DNA repair pathway in treatment-resistant cohort and the phosphorylation of the proteins involved in DNA repair such as SMC1A, HMGN1, MGMT, DDB2, MSH6 are dysregulated between the cohort suggesting role of DNA repair pathway in the treatment resistance. Kinase-substrate enrichment analysis revealed the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Conclusions: We have identified an accurate and reliable biomarker STX3 to predict CCRT resistance in cervical cancer. Further, the phosphoproteomic profiling revealed dysregulation of DNA repair pathways which may be involved in treatment resistance. Targeting the activated kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM could combat treatment resistance in cervical cancer patients.
Germline mutations in hereditary renal cell carcinoma (RCC) genes among 32,240 patients with all cancer types.
Authors: Maria Isabel Carlo, Andrew Schroeder, Semanti Mukherjee, Yelena Kemel, Ritesh R Kotecha, Chung-Han Lee, Neil J. Shah, Darren R. Feldman, Ying L Liu, Michael Francis Walsh, Alicia Latham, Martin H Voss, Ying-Bei Chen, Zsofia Kinga Stadler, Diana Mandelker, Kenneth Offit, Robert J. Motzer
Journal: Journal of Clinical Oncology (2023)

4559 Background: Germline pathogenic variants (PVs) in VHL, FH, BAP1 and others cause hereditary syndromes with increased risk of renal cell carcinoma (RCC). Defining the clinical spectrum of these syndromes has been limited by ascertainment bias and their relative rarity. Using a large population of cancer patients who underwent germline and somatic tumor testing, we analyzed the landscape of germline PVs in RCC genes in individuals with all cancer types. Methods: We identified patients with germline PVs in RCC genes ( VHL, FH, SDHB, MET, FLCN, BAP1) in the MSK-IMPACT cohort, an institutional protocol of patients who had somatic and germline sequencing. The MITF E318K variant was analyzed separately given its uncertain role in RCC risk. Objectives were to determine whether patients met clinical criteria for their respective hereditary syndromes, analyze biallelic inactivation in all tumor types, and explore underrecognized cancer associations. Fisher test was used to compare frequency of variants to population. Results: Of 32,240 patients who consented to germline results, 55% were female; most common cancer types were breast (n=3600), pancreas (n=3554), prostate (n=3427), with 1166 (3.6%) with RCC. 110 (0.34%) had a germline variant in a RCC syndrome gene ( BAP1=26, SDHB=24, FH=24, FLCN=19, VHL=16, MET=1). Of 110 germline positive, 56% met clinical criteria for their hereditary syndrome, and 40% had RCC. For VHL, FH, SDHB and MET, a high proportion of patients met criteria for their hereditary syndromes, but this was much less for FLCN (Birt-Hogg-Dubé) and BAP1. Biallelic inactivation in the tumor, supporting causality, was very high except in FLCN. Possible novel cancer associations were liver cancer in BAP1 (n=5;19%) and colon cancer in FLCN (n=4;17%). Additionally, 114 patients had the MITF E318K variant; which was not enriched in RCC cases (only 1 RCC) compared to other cancers or population control (odds ratio 0.45; p-value = 0.16, 95% confidence interval: 0.1 -1.2). Conclusions: Germline analysis in a large pan-cancer cohort identifies a high prevalence of patients with hereditary RCC syndromes, variability in clinical phenotype and suggestion of novel cancer associations. The low number of MITF E318K variant carriers in RCC cases calls into question its role in RCC risk and warrants further study. [Table: see text]
Dosing patterns and treatment patterns in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.
Authors: Joanna P. MacEwan, Michelle Silver, Paul Cockrum, Chad Sanders, George P. Kim
Journal: Journal of Clinical Oncology (2023)

e16255 Background: While FOLFIRINOX (FFX) demonstrated a significant overall and progression-free survival benefit vs. gemcitabine in the PRODIGE 4/ACCORD 11 trial among previously untreated patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC), treatment with FFX was associated with a higher rate of grade 3/4 adverse events (AEs). In an effort to reduce toxicity, modified FFX (mFFX) regimens that employ lower doses of components of the regimen have been developed. To better understand the frequency and degree of dose modifications in practice, we examined real-world (RW) dosing patterns among mPDAC pts receiving FFX in first line (1L). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. Doses of each FFX component were measured during cycles in which pts received all four components of the FFX regimen on the same date. mFFX was defined as administration of &lt; 150mg/m 2 of irinotecan or &lt; 2,720mg/m 2 5-FU total during cycle 1. Results: Of the 1,326 pts eligible meeting inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The bolus of 5-FU was frequently omitted—only 20% (262 pts) received it in the first cycle. If pts received the bolus, they did not receive the 5-FU infusion, with the exception of 1 pt. For pts receiving at least two cycles, the percentage of pts with dose reductions of ≥10% (≥20%) between the first and last cycle were 20% (11%) for the 5-FU infusion, 18% (13%) for the 5-FU bolus, 34% (21%) for irinotecan, 12% (9%) for leucovorin, and 40% (28%) for oxaliplatin. Median starting doses were 2400, 401, 152, 399, and 85 mg/m 2 for the 5-FU infusion, bolus 5-FU, irinotecan, leucovorin, and oxaliplatin components, respectively. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m 2 for 5-FU, 179 mg/m 2 for leucovorin, 38 mg/m 2 for oxaliplatin, and 73 mg/m 2 for irinotecan. Conclusions: In a RW cohort of pts with mPDAC treated with 1L FFX, almost all received a modified version of the regimen. The 5-FU bolus was omitted for most pts. Doses of other components fell over time for a notable percentage of patients, which may reflect clinician efforts to manage FFX toxicity.
The association of HIV and other risk factors with triple-negative breast cancer in South African women.
Authors: Jacob Dubner, Alfred I. Neugut, Maureen Joffe, Daniel O'Neil, Oluwatosin Ayeni, Wenlong Carl Chen, Ines Buccimazza, Sharon Čačala, Laura Stopforth, Hayley Farrow, Sarah Nietz, Boitumelo Phakathi, Judith Jacobson, Katherine D. Crew, Paul Ruff, Herbert Cubasch, Yoanna S Pumpalova
Journal: Journal of Clinical Oncology (2023)

6583 Background: Breast cancer (BC) mortality in South Africa (SA) is double that of the United States. The aggressive triple-negative breast cancer (TNBC) subtype comprises 20.9% of BC cases among Black women in Southern Africa. SA has the second highest HIV prevalence worldwide, but if and how HIV affects the risk of developing TNBC is not well understood. Methods: Using the South African Breast Cancer and HIV Outcomes (SABCHO) prospective cohort of newly diagnosed BC patients from six public hospitals in SA, we evaluated the association of HIV with risk of TNBC relative to other BC subtypes. We developed multivariable logistic regression models to test for this association while adjusting for key demographic and reproductive risk factors. Results: Of 3,883 women with BC, 16.4% had TNBC and 23.0% were HIV-positive. The overall median age of BC diagnosis was 55 years. Among HIV positive patients, the median age of BC diagnosis was 45 years, without a difference between TNBC and non-TNBC cases (p = 0.244). Only 7.2% of women were nulliparous (4.6% in TNBC and 7.6% in non-TNBC subgroups). Of women who had at least 1 full-term pregnancy, 11.2% did not breastfeed, without a difference between TNBC and non-TNBC cases (p = 0.292). In our final multivariable logistic regression model, HIV-positive status was associated with increased risk of TNBC relative to non-TNBC (OR: 1.40; 95% CI: 1.12-1.74, compared to HIV-negative with BC). Parity without breastfeeding was also associated with increased risk of TNBC relative to non-TNBC (OR: 1.72; 95% CI: 1.07-2.84, compared to nulliparous with BC). HIV status and the combined parity/breastfeeding variable had no statistically significant interaction. In exploratory analyses, measures of HIV control at time of BC diagnosis were not associated with BC subtype. Conclusions: In this large prospective case-only study conducted in SA, we found that women living with HIV were more likely than HIV-negative women to have TNBC (relative to other BC subtypes), regardless of the extent of HIV control. Whether this relationship is mediated by immune mechanisms or other factors should be the focus of future research. Our findings highlight the importance of rigorous BC screening and early detection among HIV-positive women given their increased relative risk of developing TNBC. [Table: see text]